The frontal lobes reach their highest development in man, in whom they are thought to provide the neural basis for the analysis of past and future actions, the programming of sequential behaviors toward long-range goals, and the regulation of socially and culturally appropriate behavior. The ultimate goal of this research program is to understand the frontal lobes and their contribution to higher-order cognitive functions by detailed experimental study of its anatomy, physiology, neurochemistry and behavioral expression in nonhuman primates. The same studies should provide a neurobiological basis for understanding a variety of behavioral disorders that reflect disease in the frontal cortex and anatomically related structures such as the basal ganglia and basal forebrain. This program has evolved during the last decade to its present focus on: (1) anatomical organization with particular emphasis on microstructural analysis of the topographic, laminar and columnar organization, and degree of collateralization of prefrontal cortical connections using advanced neuroanatomical tracing techniques including autoradiography, fluorescent tracers, and horseradish peroxidase histochemistry; (2) neurochemical organization of prefrontal pathways including neurotransmitters, enzymes and receptors using immunohistochemistry, electron microscopy, and receptor autoradiography; (3) functional analysis of prefrontal cortex using lesion behavioral analysis, 2-deoxyglucose autoradiography for mapping metabolic activity and electrophysiology alone or in combination with anatomical methods; and (4) comparative and life-span developmental studies to establish a link between studies of prefrontal cortex in nonhuman primates and in man by analysis of a variety of behaviors common to both species. All experiments are conducted on rhesus monkeys whose association cortex including the prefrontal cortex is well developed and who are unexcelled laboratory animal models for the study of cortical function. By design, our strategy is multidisciplinary, but each project intersects with every other, both conceptually and technically. The proposed studies should enrich our understanding of the neural circuits and cellular basis of cognitive functions and their breakdown in mental disease.